Mast cells express fibronectin-receptor integrins on the cell surface, which are involved in cellular activation. In this study rat and mouse mast cells adhered to fibronectin through very late antigen 4, 5 (beta 1 integrin) and vitronectin receptor (beta 3 integrin), and engagement of these receptors promoted cellular degranulation induced by cross-linking of the high-affinity IgE receptor. Blocking of these adhesion molecules by monoclonal antibodies remarkably reduced passive cutaneous anaphylaxis reaction in vivo. On fibronectin, cytokine release from mast cells on IgE receptor aggregation was also enhanced, but not the expression of cytokine genes, with the exception of interleukin-3. Interleukin-3 gene expression was constitutively observed in mouse-cultured mast cells and significantly increased on fibronectin with a prolonged survival of the cells, suggesting that the autocrine or paracrine system of interleukin-3 secretion contributes to the prolonged survival of mast cells on fibronectin. Our findings presented here clearly indicate that the engagement of fibronectin-receptor integrins on mast cells increases the sensitivity of the cells for cellular activation. Taking into consideration the fact that mast cells in the microenvironment are actually surrounded by other cells and extracellular matrix proteins, we identified significant roles of adhesion molecules on mast cells in the allergic state, and we hope to develop new strategies to manipulate these molecules for medical intervention in allergy.